A condensate-hardening drug blocks RSV replication in vivo

Jennifer Risso-Ballester1, Marie Galloux2, Jingjing Cao3, Ronan Le Goffic2, Fortune Hontonnou2, Aude Jobart-Malfait1, Aurore Desquesnes1, Svenja M Sake4, Sibylle Haid4, Miaomiao Du3, Xiumei Zhang3, Huanyun Zhang3, Zhaoguo Wang5, Vincent Rincheval1, Youming Zhang3, Thomas Pietschmann4, Jean-François Eléouët6, Marie-Anne Rameix-Welti7,8, Ralf Altmeyer9,10

  1. Université Paris-Saclay, INSERM, Université de Versailles St Quentin, UMR 1173 (2I), Versailles, France.
  2. Unité de Virologie et Immunologie Moléculaires (UR892), INRAE, Université Paris-Saclay, Jouy-en-Josas, France.
  3. Helmholtz International Lab for Anti-Infectives, State Key Laboratory of Microbial Technology, Microbial Technology Institute, Shandong University, Qingdao, P. R. China.
  4. Helmholtz International Lab for Anti-Infectives, Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany.
  5. Qingdao Municipal Center for Disease Control and Prevention, Qingdao, P. R. China.
  6. Unité de Virologie et Immunologie Moléculaires (UR892), INRAE, Université Paris-Saclay, Jouy-en-Josas, France. jean-francois.eleouet@inrae.fr.
  7. Université Paris-Saclay, INSERM, Université de Versailles St Quentin, UMR 1173 (2I), Versailles, France. marie-anne.rameix-welti@uvsq.fr.
  8. Assistance Publique des Hôpitaux de Paris, Université Paris Saclay, Hôpital Ambroise Paré, Laboratoire de Microbiologie, Boulogne-Billancourt, France. marie-anne.rameix-welti@uvsq.fr.
  9. Helmholtz International Lab for Anti-Infectives, State Key Laboratory of Microbial Technology, Microbial Technology Institute, Shandong University, Qingdao, P. R. China. ralf.marius.altmeyer@gmail.com.
  10. School of Public Health, University of Hong Kong, Hong Kong SAR, P. R. China. ralf.marius.altmeyer@gmail.com.

Abstract

Biomolecular condensates have emerged as an important subcellular organizing principle1. Replication of many viruses, including human respiratory syncytial virus (RSV), occurs in virus-induced compartments called inclusion bodies (IBs) or viroplasm2,3. IBs of negative-strand RNA viruses were recently shown to be biomolecular condensates that form through phase separation4,5. Here we report that the steroidal alkaloid cyclopamine and its chemical analogue A3E inhibit RSV replication by disorganizing and hardening IB condensates. The actions of cyclopamine and A3E were blocked by a point mutation in the RSV transcription factor M2-1. IB disorganization occurred within minutes, which suggests that these molecules directly act on the liquid properties of the IBs. A3E and cyclopamine inhibit RSV in the lungs of infected mice and are condensate-targeting drug-like small molecules that have in vivo activity. Our data show that condensate-hardening drugs may enable the pharmacological modulation of not only many previously undruggable targets in viral replication but also transcription factors at cancer-driving super-enhancers6.

Presented By Jennifer Risso Ballester

Medicine, Cell & Developmental Bio, BiochemistryNicholas Liao2021-07 (Jul)